122 results on '"Kayagaki, Nobuhiko"'
Search Results
102. Expression of Fas Ligand and Its Receptor in Cutaneous Lupus: Implication in Tissue Injury
- Author
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Nakajima, Michiko, primary, Nakajima, Atsuo, additional, Kayagaki, Nobuhiko, additional, Honda, Mitsuyoshi, additional, Yagita, Hideo, additional, and Okumura, Ko, additional
- Published
- 1997
- Full Text
- View/download PDF
103. Antitumor effect of locally produced CD95 ligand
- Author
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Seino, Ken-Ichiro, primary, Kayagaki, Nobuhiko, additional, Okumura, Ko, additional, and Yagita, Hideo, additional
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- 1997
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104. Contribution of Fas ligand to cardiac allograft rejection
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Seino, Kenichiro, primary, Kayagaki, Nobuhiko, additional, Bashuda, Hisashi, additional, Okumura, Ko, additional, Yagita, Hideo, additional, and Hamaoka, T., additional
- Published
- 1996
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105. Activation-induced peripheral blood T cell apoptosis is Fas independent in HIV-infected individuals
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Katsikis, Peter D., primary, Garcfa-Ojeda, Marcos E., additional, Wunderlich, Eric S., additional, Smith, Craig A., additional, Yagita, Hideo, additional, Okumura, Ko, additional, Kayagaki, Nobuhiko, additional, Alderson, Mark, additional, Herzenberg, Leonore A., additional, Herzenberg, Leonard A., additional, and Lanier, L., additional
- Published
- 1996
- Full Text
- View/download PDF
106. Yersinia virulence factor YopJ acts as a deubiquitinase to inhibit NF-κB activation.
- Author
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Honglin Zhou, Monack, Denise M., Kayagaki, Nobuhiko, Wertz, Ingrid, Jianpin Yin, Wolf, Beni, and Dixit, Vishva M.
- Subjects
YERSINIA ,NF-kappa B ,PROTEIN kinases ,YERSINIA diseases ,IMMUNOLOGY - Abstract
The bacterial pathogens of the genus Yersinia, the causative agents of plague, septicemia, and gastrointestinal syndromes, use a type III secretion system to inject virulence factors into host target cells. One virulence factor, YopJ, is essential for the death of infected macrophages and can block host proinflammatory responses by inhibiting both the nuclear factor κB (NF-κB) and mitogen-activated protein kinase pathways, which might be important for evasion of the host immune response and aid in establishing a systemic infection. Here, we show that YopJ is a promiscuous deubiquitinating enzyme that negatively regulates signaling by removing ubiquitin moieties from critical proteins, such as TRAF2, TRAF6, and IκBα. In contrast to the cylindromatosis tumor suppressor CYLD, which attenuates NF-κB signaling by selectively removing K63-linked polyubiquitin chains that activate IκB kinase, YopJ also cleaves K48-linked chains and thereby inhibits proteasomal degradation of IκBα. YopJ, but not a catalytically inactive YopJ mutant, promoted deubiquitination of cellular proteins and cleaved both K48- and K63-linked polyubiquitin. Moreover, an in vitro assay was established to demonstrate directly the deubiquitinating activity of purified YopJ. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
107. Sensitization of human glioblastomas to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by NF-κB inhibitors.
- Author
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Kasuga, Chinatsu, Ebata, Tomohiko, Kayagaki, Nobuhiko, Yagita, Hideo, Hishii, Makoto, Aral, Hajime, Sato, Kiyoshi, and Okumura, Ko
- Published
- 2004
- Full Text
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108. Antiviral response by natural killer cells through TRAIL gene induction by IFN-α/β.
- Author
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Sato, Kojiro, Hida, Shigeaki, Takayanagi, Hiroshi, Yokochi, Taeko, Kayagaki, Nobuhiko, Takeda, Kazuyoshi, Yagita, Hideo, Okumura, Ko, Tanaka, Nobuyuki, Taniguchi, Tadatsugu, and Ogasawara, Kouetsu
- Published
- 2001
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109. The alteration of fas receptor and ligand system in hepatocellular carcinomas: How do hepatoma cells escape from the host immune surveillance in vivo?
- Author
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Nagao, Mitsuo, Nakajima, Yoshiyuki, Hisanaga, Michiyoshi, Kayagaki, Nobuhiko, Kanehiro, Hiromichi, Aomatsu, Yukio, Ko, Saiho, Yagita, Hideo, Yamada, Takatsugu, Okumura, Ko, and Nakano, Hiroshige
- Published
- 1999
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110. Differential Effects of Anti-Fas Ligand and Anti-Tumor Necrosis Factor a Antibodies on Acute Graft-Versus-Host Disease Pathologies
- Author
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Hattori, Koichi, Hirano, Takao, Miyajima, Hiroaki, Yamakawa, Norifumi, Tateno, Masatoshi, Oshimi, Kazuo, Kayagaki, Nobuhiko, Yagita, Hideo, and Okumura, Ko
- Abstract
Both tumor necrosis factor a (TNFa) and Fas ligand (FasL) have been implicated in the pathogenesis of graft-versus-host disease (GVHD). In this study, we examined the ameliorating effects of neutralizing anti-FasL and/or anti-TNFa monoclonal antibody (MoAb) in a lethal acute GVHD model in mice. Whereas the treatment with either anti-FasL or anti-TNFa MoAb alone significantly delayed the mortality and improved the body weight, a complete protection was achieved by the administration of both MoAbs. Pathological examination indicated differential effects of anti-FasL or anti-TNFa MoAb on GVHD-associated pathologies. Hepatic lesion was improved by anti-FasL but not anti-TNFa MoAb. In contrast, intestinal lesion was improved by anti-TNFa but not anti-FasL MoAb. Cutaneous and splenic lesions were improved by either MoAb. The combination of both MoAbs improved all these lesions. These results indicate that FasL and TNFa differentially contribute to the GVHD pathologies and a complete protection from mortality can be achieved by neutralization of both FasL and TNFa.
- Published
- 1998
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111. SOLUBLE FORMS OF CD95 AND CD95 LIGAND AFTER LIVING RELATED LIVER TRANSPLANTATION1.
- Author
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Seino, Ken-Ichiro, Kayagaki, Nobuhiko, Yamaguchi, Noriko, Takada, Yasutsugu, Uyama, Shiro, Kiuchi, Tetsuya, Tanaka, Koichi, Yagita, Hideo, Okumura, Ko, and Fukao, Katashi
- Published
- 1999
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112. IRF2 transcriptionally induces GSDMDexpression for pyroptosis
- Author
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Kayagaki, Nobuhiko, Lee, Bettina L., Stowe, Irma B., Kornfeld, Opher S., O'Rourke, Karen, Mirrashidi, Kathleen M., Haley, Benjamin, Watanabe, Colin, Roose-Girma, Merone, Modrusan, Zora, Kummerfeld, Sarah, Reja, Rohit, Zhang, Yafei, Cho, Vicky, Andrews, T. Daniel, Morris, Lucy X., Goodnow, Christopher C., Bertram, Edward M., and Dixit, Vishva M.
- Abstract
Pyroptosis requires the induction of gasdermin D expression by the transcription factor IRF2.
- Published
- 2019
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113. Epigenetic and transcriptional control of gasdermins.
- Author
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Cadena, Cristhian, Kornfeld, Opher S., Lee, Bettina L., and Kayagaki, Nobuhiko
- Subjects
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APOPTOSIS , *EPIGENETICS , *HOMEOSTASIS , *CELL death , *PYROPTOSIS , *BLEPHAROPTOSIS - Abstract
Cells undergo an inflammatory programmed lytic cell death called 'pyroptosis' (with the Greek roots 'fiery'), often featuring morphological hallmarks such as large ballooning protrusions and subsequent bursting. Originally described as a caspase-1-dependent cell death in response to bacterial infection, pyroptosis has since been re-defined in 2018 as a cell death dependent on plasma membrane pores by a gasdermin (GSDM) family member [1,2]. GSDMs form pores in the plasma membrane as well as organelle membranes, thereby initiating membrane destruction and the rapid and lytic demise of a cell. The gasdermin family plays a profound role in the execution of pyroptosis in the context of infection, inflammation, tumor pathogenesis, and anti-tumor therapy. More recently, cell-death-independent functions for some of the GSDMs have been proposed. Therefore, a comprehensive understanding of gasdermin gene regulation, including mechanisms in both homeostatic conditions and during inflammation, is essential. In this review, we will summarize the role of gasdermins in pyroptosis and focus our discussion on the transcriptional and epigenetic mechanisms controlling the expression of GSDMs. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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114. Pathogen blockade of TAK1 triggers caspase-8–dependent cleavage of gasdermin D and cell death.
- Author
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Orning, Pontus, Weng, Dan, Starheim, Kristian, Ratner, Dmitry, Best, Zachary, Lee, Bettina, Brooks, Alexandria, Xia, Shiyu, Wu, Hao, Kelliher, Michelle A., Berger, Scott B., Gough, Peter J., Bertin, John, Proulx, Megan M., Goguen, Jon D., Kayagaki, Nobuhiko, Fitzgerald, Katherine A., and Lien, Egil
- Subjects
- *
PATHOGENIC microorganisms , *CASPASES , *CELL death , *MACROPHAGES , *KINASES , *YERSINIA , *INFLAMMASOMES , *INTERLEUKIN-1 - Abstract
Limited proteolysis of gasdermin D (GSDMD) generates an N-terminal pore-forming fragment that controls pyroptosis in macrophages. GSDMD is processed via inflammasome-activated caspase-1 or -11. It is currently unknown whether macrophage GSDMD can be processed by other mechanisms. Here, we describe an additional pathway controlling GSDMD processing. The inhibition of TAK1 or IkB kinase (IKK) by the Yersinia effector protein YopJ elicits RIPK1- and caspase-8–dependent cleavage of GSDMD, which subsequently results in cell death. GSDMD processing also contributes to the NLRP3 inflammasome–dependent release of interleukin-1b (IL-1b). Thus, caspase-8 acts as a regulator of GSDMD-driven cell death. Furthermore, this study establishes the importance of TAK1 and IKK activity in the control of GSDMD cleavage and cytotoxicity. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
115. Control of Cell Death in Health and Disease.
- Author
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Kayagaki N, Webster JD, and Newton K
- Subjects
- Humans, Animals, Mice, Cell Death, Inflammation, Mammals, Nerve Growth Factors, Cell Adhesion Molecules, Neuronal, Apoptosis, Autoimmunity
- Abstract
Apoptosis, necroptosis, and pyroptosis are genetically programmed cell death mechanisms that eliminate obsolete, damaged, infected, and self-reactive cells. Apoptosis fragments cells in a manner that limits immune cell activation, whereas the lytic death programs of necroptosis and pyroptosis release proinflammatory intracellular contents. Apoptosis fine-tunes tissue architecture during mammalian development, promotes tissue homeostasis, and is crucial for averting cancer and autoimmunity. All three cell death mechanisms are deployed to thwart the spread of pathogens. Disabling regulators of cell death signaling in mice has revealed how excessive cell death can fuel acute or chronic inflammation. Here we review strategies for modulating cell death in the context of disease. For example, BCL-2 inhibitor venetoclax, an inducer of apoptosis, is approved for the treatment of certain hematologic malignancies. By contrast, inhibition of RIPK1, NLRP3, GSDMD, or NINJ1 to limit proinflammatory cell death and/or the release of large proinflammatory molecules from dying cells may benefit patients with inflammatory diseases.
- Published
- 2024
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116. Cell death.
- Author
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Newton K, Strasser A, Kayagaki N, and Dixit VM
- Subjects
- Humans, Apoptosis, Ferroptosis, Homeostasis, Pyroptosis, Cell Death, Signal Transduction
- Abstract
Cell death supports morphogenesis during development and homeostasis after birth by removing damaged or obsolete cells. It also curtails the spread of pathogens by eliminating infected cells. Cell death can be induced by the genetically programmed suicide mechanisms of apoptosis, necroptosis, and pyroptosis, or it can be a consequence of dysregulated metabolism, as in ferroptosis. Here, we review the signaling mechanisms underlying each cell-death pathway, discuss how impaired or excessive activation of the distinct cell-death processes can promote disease, and highlight existing and potential therapies for redressing imbalances in cell death in cancer and other diseases., Competing Interests: Declaration of interests K.N., N.K., and V.M.D. are employees of Genentech. A.S. is an employee of WEHI: Walter and Eliza Hall Institute of Medical Research, which received royalties and milestone payments from Venetoclax. A.S. has also received funding for some of his research from Servier Laboratories., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
117. Inhibiting membrane rupture with NINJ1 antibodies limits tissue injury.
- Author
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Kayagaki N, Stowe IB, Alegre K, Deshpande I, Wu S, Lin Z, Kornfeld OS, Lee BL, Zhang J, Liu J, Suto E, Lee WP, Schneider K, Lin W, Seshasayee D, Bhangale T, Chalouni C, Johnson MC, Joshi P, Mossemann J, Zhao S, Ali D, Goldenberg NM, Sayed BA, Steinberg BE, Newton K, Webster JD, Kelly RL, and Dixit VM
- Subjects
- Animals, Mice, Alanine Transaminase, Alarmins, Aspartate Aminotransferases, Cell Adhesion Molecules, Neuronal antagonists & inhibitors, Cell Adhesion Molecules, Neuronal deficiency, Cell Adhesion Molecules, Neuronal immunology, Cell Adhesion Molecules, Neuronal ultrastructure, Cell Death, Concanavalin A, Galactosamine, Hepatocytes pathology, Hepatocytes ultrastructure, Lactate Dehydrogenases, Microscopy, Electron, Neutrophil Infiltration, Antibodies, Monoclonal immunology, Cell Membrane pathology, Cell Membrane ultrastructure, Inflammation pathology, Liver pathology, Nerve Growth Factors antagonists & inhibitors, Nerve Growth Factors deficiency, Nerve Growth Factors immunology, Nerve Growth Factors ultrastructure, Reperfusion Injury pathology
- Abstract
Plasma membrane rupture (PMR) in dying cells undergoing pyroptosis or apoptosis requires the cell-surface protein NINJ1
1 . PMR releases pro-inflammatory cytoplasmic molecules, collectively called damage-associated molecular patterns (DAMPs), that activate immune cells. Therefore, inhibiting NINJ1 and PMR may limit the inflammation that is associated with excessive cell death. Here we describe an anti-NINJ1 monoclonal antibody that specifically targets mouse NINJ1 and blocks oligomerization of NINJ1, preventing PMR. Electron microscopy studies showed that this antibody prevents NINJ1 from forming oligomeric filaments. In mice, inhibition of NINJ1 or Ninj1 deficiency ameliorated hepatocellular PMR induced with TNF plus D-galactosamine, concanavalin A, Jo2 anti-Fas agonist antibody or ischaemia-reperfusion injury. Accordingly, serum levels of lactate dehydrogenase, the liver enzymes alanine aminotransaminase and aspartate aminotransferase, and the DAMPs interleukin 18 and HMGB1 were reduced. Moreover, in the liver ischaemia-reperfusion injury model, there was an attendant reduction in neutrophil infiltration. These data indicate that NINJ1 mediates PMR and inflammation in diseases driven by aberrant hepatocellular death., (© 2023. The Author(s).)- Published
- 2023
- Full Text
- View/download PDF
118. Discovery of a caspase cleavage motif antibody reveals insights into noncanonical inflammasome function.
- Author
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Davies CW, Stowe I, Phung QT, Ho H, Bakalarski CE, Gupta A, Zhang Y, Lill JR, Payandeh J, Kayagaki N, and Koerber JT
- Subjects
- Amino Acid Sequence, Caspases chemistry, Models, Molecular, Peptides chemistry, Peptides metabolism, Protein Binding, Protein Interaction Domains and Motifs, Proteolysis, Signal Transduction, Structure-Activity Relationship, Amino Acid Motifs, Antibodies chemistry, Antibodies metabolism, Binding Sites, Caspases metabolism, Inflammasomes metabolism
- Abstract
Inflammasomes sense a number of pathogen and host damage signals to initiate a signaling cascade that triggers inflammatory cell death, termed pyroptosis. The inflammatory caspases (1/4/5/11) are the key effectors of this process through cleavage and activation of the pore-forming protein gasdermin D. Caspase-1 also activates proinflammatory interleukins, IL-1β and IL-18, via proteolysis. However, compared to the well-studied apoptotic caspases, the identity of substrates and therefore biological functions of the inflammatory caspases remain limited. Here, we construct, validate, and apply an antibody toolset for direct detection of neo-C termini generated by inflammatory caspase proteolysis. By combining rabbit immune phage display with a set of degenerate and defined target peptides, we discovered two monoclonal antibodies that bind peptides with a similar degenerate recognition motif as the inflammatory caspases without recognizing the canonical apoptotic caspase recognition motif. Crystal structure analyses revealed the molecular basis of this strong yet paradoxical degenerate mode of peptide recognition. One antibody selectively immunoprecipitated cleaved forms of known and unknown inflammatory caspase substrates, allowing the identification of over 300 putative substrates of the caspase-4 noncanonical inflammasome, including caspase-7. This dataset will provide a path toward developing blood-based biomarkers of inflammasome activation. Overall, our study establishes tools to discover and detect inflammatory caspase substrates and functions, provides a workflow for designing antibody reagents to study cell signaling, and extends the growing evidence of biological cross talk between the apoptotic and inflammatory caspases., Competing Interests: Competing interest statement: All authors are employees of Genentech, Inc.
- Published
- 2021
- Full Text
- View/download PDF
119. NINJ1 mediates plasma membrane rupture during lytic cell death.
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Kayagaki N, Kornfeld OS, Lee BL, Stowe IB, O'Rourke K, Li Q, Sandoval W, Yan D, Kang J, Xu M, Zhang J, Lee WP, McKenzie BS, Ulas G, Payandeh J, Roose-Girma M, Modrusan Z, Reja R, Sagolla M, Webster JD, Cho V, Andrews TD, Morris LX, Miosge LA, Goodnow CC, Bertram EM, and Dixit VM
- Subjects
- Animals, Apoptosis, Cell Adhesion Molecules, Neuronal chemistry, Cell Adhesion Molecules, Neuronal genetics, Female, Humans, Macrophages, Male, Mice, Mutation, Necrosis, Nerve Growth Factors chemistry, Nerve Growth Factors genetics, Protein Multimerization, Pyroptosis genetics, Cell Adhesion Molecules, Neuronal metabolism, Cell Death genetics, Cell Membrane metabolism, Nerve Growth Factors metabolism
- Abstract
Plasma membrane rupture (PMR) is the final cataclysmic event in lytic cell death. PMR releases intracellular molecules known as damage-associated molecular patterns (DAMPs) that propagate the inflammatory response
1-3 . The underlying mechanism of PMR, however, is unknown. Here we show that the cell-surface NINJ1 protein4-8 , which contains two transmembrane regions, has an essential role in the induction of PMR. A forward-genetic screen of randomly mutagenized mice linked NINJ1 to PMR. Ninj1-/- macrophages exhibited impaired PMR in response to diverse inducers of pyroptotic, necrotic and apoptotic cell death, and were unable to release numerous intracellular proteins including HMGB1 (a known DAMP) and LDH (a standard measure of PMR). Ninj1-/- macrophages died, but with a distinctive and persistent ballooned morphology, attributable to defective disintegration of bubble-like herniations. Ninj1-/- mice were more susceptible than wild-type mice to infection with Citrobacter rodentium, which suggests a role for PMR in anti-bacterial host defence. Mechanistically, NINJ1 used an evolutionarily conserved extracellular domain for oligomerization and subsequent PMR. The discovery of NINJ1 as a mediator of PMR overturns the long-held idea that cell death-related PMR is a passive event.- Published
- 2021
- Full Text
- View/download PDF
120. Yersinia virulence factor YopJ acts as a deubiquitinase to inhibit NF-kappa B activation.
- Author
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Zhou H, Monack DM, Kayagaki N, Wertz I, Yin J, Wolf B, and Dixit VM
- Subjects
- Bacterial Proteins chemistry, Cell Line, Deubiquitinating Enzyme CYLD, Down-Regulation, Endopeptidases chemistry, Humans, NF-kappa B metabolism, SUMO-1 Protein metabolism, Tumor Suppressor Proteins physiology, Virulence Factors chemistry, Yersinia pathogenicity, Bacterial Proteins physiology, Endopeptidases physiology, NF-kappa B antagonists & inhibitors, Ubiquitin metabolism, Virulence Factors physiology, Yersinia enzymology, Yersinia Infections enzymology
- Abstract
The bacterial pathogens of the genus Yersinia, the causative agents of plague, septicemia, and gastrointestinal syndromes, use a type III secretion system to inject virulence factors into host target cells. One virulence factor, YopJ, is essential for the death of infected macrophages and can block host proinflammatory responses by inhibiting both the nuclear factor kappaB (NF-kappaB) and mitogen-activated protein kinase pathways, which might be important for evasion of the host immune response and aid in establishing a systemic infection. Here, we show that YopJ is a promiscuous deubiquitinating enzyme that negatively regulates signaling by removing ubiquitin moieties from critical proteins, such as TRAF2, TRAF6, and IkappaBalpha. In contrast to the cylindromatosis tumor suppressor CYLD, which attenuates NF-kappaB signaling by selectively removing K63-linked polyubiquitin chains that activate IkappaB kinase, YopJ also cleaves K48-linked chains and thereby inhibits proteasomal degradation of IkappaBalpha. YopJ, but not a catalytically inactive YopJ mutant, promoted deubiquitination of cellular proteins and cleaved both K48- and K63-linked polyubiquitin. Moreover, an in vitro assay was established to demonstrate directly the deubiquitinating activity of purified YopJ.
- Published
- 2005
- Full Text
- View/download PDF
121. BAFF/BLyS receptor 3 binds the B cell survival factor BAFF ligand through a discrete surface loop and promotes processing of NF-kappaB2.
- Author
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Kayagaki N, Yan M, Seshasayee D, Wang H, Lee W, French DM, Grewal IS, Cochran AG, Gordon NC, Yin J, Starovasnik MA, and Dixit VM
- Subjects
- Amino Acid Sequence, Animals, Apoptosis, B-Cell Activating Factor, B-Cell Activation Factor Receptor, B-Lymphocytes cytology, Binding Sites, Cell Line, Female, Ligands, Lupus Erythematosus, Systemic immunology, Mice, Mice, Inbred A, Mice, Inbred C57BL, Mice, Inbred NZB, Mice, Knockout, Mice, Mutant Strains, Models, Molecular, Molecular Sequence Data, NF-kappa B p52 Subunit, Protein Processing, Post-Translational, Protein Structure, Tertiary, Receptors, Tumor Necrosis Factor chemistry, Receptors, Tumor Necrosis Factor genetics, Signal Transduction, B-Lymphocytes immunology, B-Lymphocytes metabolism, Membrane Proteins metabolism, NF-kappa B metabolism, Receptors, Tumor Necrosis Factor metabolism, Tumor Necrosis Factor-alpha metabolism
- Abstract
The TNF-like ligand BAFF/BLyS is a potent survival factor for B cells. It binds three receptors: TACI, BCMA, and BR3. We show that BR3 signaling promotes processing of the transcription factor NF-kappaB2/p100 to p52. NF-kappaB2/p100 cleavage was abrogated in B cells from A/WySnJ mice possessing a mutant BR3 gene, but not in TACI or BCMA null B cells. Furthermore, wild-type mice injected with BAFF-neutralizing BR3-Fc protein showed reduced basal NF-kappaB2 activation. BR3-Fc treatment of NZB/WF1 mice, which develop a fatal lupus-like syndrome, inhibited NF-kappaB2 processing and attenuated the disease process. Since inhibiting the BR3-BAFF interaction has therapeutic ramifications, the ligand binding interface of BR3 was investigated and found to reside within a 26 residue core domain. When stabilized within a structured beta-hairpin peptide, six of these residues were sufficient to confer binding to BAFF.
- Published
- 2002
- Full Text
- View/download PDF
122. Characterization of the in vivo function of TNF-alpha-related apoptosis-inducing ligand, TRAIL/Apo2L, using TRAIL/Apo2L gene-deficient mice.
- Author
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Sedger LM, Glaccum MB, Schuh JC, Kanaly ST, Williamson E, Kayagaki N, Yun T, Smolak P, Le T, Goodwin R, and Gliniak B
- Subjects
- Animals, Apoptosis Regulatory Proteins, Bone Density, Female, Glycoproteins physiology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neoplasm Transplantation, Neoplasms, Experimental immunology, Osteoclasts physiology, Osteoprotegerin, Receptors, Cytoplasmic and Nuclear physiology, Receptors, Tumor Necrosis Factor, TNF-Related Apoptosis-Inducing Ligand, Membrane Glycoproteins physiology, Tumor Necrosis Factor-alpha physiology
- Abstract
To define the normal physiological role for the TRAIL/Apo2L in vivo, we generated TRAIL/Apo2L gene-targeted mice. These mice develop normally and show no defects in lymphoid or myeloid cell homeostasis or function. Although TRAIL/Apo2L kills transformed cells in vitro, TRAIL/Apo2L(-/-) mice do not spontaneously develop overt tumors at an early age. However, in the A20 B cell lymphoma-transferred tumor model, TRAIL/Apo2L(-/-) mice are clearly more susceptible to death from overwhelming tumor burden, due to increased lymphoma load in the liver. A20 tumors are susceptible to TRAIL/Apo2L killing in vitro, indicating that TRAIL/Apo2L may act directly to control A20 cells in vivo. Despite the fact that TRAIL binds osteoprotegerin and osteoprotegerin-transgenic mice are osteopetrotic, TRAIL/Apo2L(-/-) mice show no evidence of altered gross bone density, and no alterations in frequency or in vitro differentiation of bone marrow precursor osteoclasts. Moreover, leucine zipper TRAIL has no toxicity when repeatedly administered to osteoprotegerin(-/-) mice. Thus, TRAIL/Apo2L is important in controlling tumors in vivo, but is not an essential regulator of osteoprotegerin-mediated biology, under normal physiological conditions.
- Published
- 2002
- Full Text
- View/download PDF
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